The present invention relates to organic synthesis, and is in particular a method of preparation of substituted halogenodiazines and unfused heteropolycyclic compounds.
Halogenodiazines are important intermediate compounds in organic synthesis. Halogen atoms, F, Cl, Br and I, adjacent to ring nitrogens are easily replaced by a variety of common nucleophiles such as hydroxide ions, alkoxides, mercaptides, and amines. For example, L. Strekowski, et al., in Roczniki Chem. 49, 1017 (1975), reported a method for the synthesis of methoxy-and dimethylamino-5-bromopyrimidines in which they reacted 2,4-dichloro-5-bromopyrimidine with dimethylamine and sodium methoxide to produce the corresponding substituted pyrimidines. L. Strekowski, et al., found that the halogen atom in the C-4 position is more labile toward nucleophilic displacement than the halogen at the C-2 position, and that the reaction is regioselective.
Before the nucleophilic substitution of the halogen ortho to nitrogen in the diazine is undertaken, simple halogenodiazines can be modified by reaction with organometallic reagents. Brown, Cowden and Strekowski, in Aust. J. Chem., 35, 1209 (1982), showed that 2-chloropyrimidine could be treated with thien-2-yl lithium or thiazol-2-yl lithium to produce 2-chloro-4-(thien-2'-yl)-3,4-dihydropyrimidine and 2-chloro-4-(thiazol-2'-yl)-3,4dihydropyrimidine, respectively. The nucleophilic anion attacks the pyrimidine ring ortho to the ring nitrogen. The resulting dihydropyrimidines were oxidized by potassium permanganate (KMnO.sub.4) in acetone to yield the substituted halogenopyrimidines.
The dehydrogenation of substituted halogenodihydropyrimidines with KMnO.sub.4 is synthetically difficult for several reasons. First, manganese dioxide, a KMnO.sub.4 reaction byproduct, is a finely dispersed solid which is difficult to remove from the reaction mixture. Dehydrogenation with KMnO.sub.4 also requires the isolation of the dihydro-addition product of the organolithium reagent with halogenopyrimidine before the oxidation step. This is necessary because KMnO.sub.4 is not soluble in ether solvents normally used for reactions with organolithium reagents. The solvent removal step is time consuming and contributes to a lower yield. The oxidation typically is performed at elevated temperature, resulting in further side products and lower yield. Oxidation of the dihydropyrimidine with KMnO.sub.4 also requires large volumes of anhydrous acetone. For example, Brown, et al. used 1200 ml of anhydrous acetone solvent in the dehydrogenation of 4.6 grams of 2-chloro-4-(thien-2'-yl)-3,4-dihydropyrimidine. If the solvent is wet, the halogenodihydropyrimidine is hydrolyzed to the hydroxy compound, 2-hydroxy-4-(thien-2'-yl)-3,4-dihydropyrimidine. Furthermore, it is difficult to prepare large volumes of strictly anhydrous acetone.
In addition, only a small amount of product is recovered due to the synthetic difficulties involved in the two step procedure requiring the addition of an organolithium reagent and subsequent dehydrogenation of the addition product under different solvent conditions. Brown, et al. reported a yield of approximately 37% for the synthesis of 2-chloro-4-(thiazol-2'-yl)-pyrimidine using potassium permanganate as the oxidizing reagent. Similarly, S. Gronowitz and J. Roe, in Acta Chem. Scand. 19, 1741 (1965) reported yields of 37% for the two step synthesis of 4-(2'-thienyl)-5-bromopyrimidine and of 47% for 4-(2'-thienyl)-2-bromopyrimidine, prepared using potassium permanganate to dehydrogenate the organolithium addition product.
In a variation of the two step procedure to produce substituted halogenopyrimidines, Elmoghayar and coworkers (Acta Chem. Scand. B 37, 160 (1983); Acta Chem. Scand. B 37 109 (1983)) reacted 2,4-dichloro-5-halopyrimidine with a Grignard reagent in the presence of a catalyst, dichloro-[1,3-bis(diphenylphosphinopropane]nickel (II) [NiCl2 (dppp)]. When alkyl Grignard reagents are used, the product is a mixture of 2,4-dialkyl-5-halopyrimidine and 2,4-dichloro-5-halo-6-alkyl-1,6-dihydropyrimidine in a ratio of 7:1 (47%:7%). When an aralkyl Grignard reagent is used, the only product recovered is 2,4-dichloro-5-halo-6-aralkyl-1,6-dihydropyrimidine, which is dehydrogenated in a separate step with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), with an overall yield of 34%. Similarly, Rise and coworkers, Acta Chem. Scand. B 37 613 (1983), reacted 5-cyano-2-methylthiopyrimidine with a Grignard reagent to form 5-cyano-2-methylthio-4-phenyl-3,4-dihydropyrimidine, which was isolated and then dehydrogenated with DDQ in a second step to 5-cyano-2-methylthio-4-phenylpyrimidine, with a yield of 40%. 5-Cyano-4-methylthiopyrimidine was similarly prepared, with a yield of 45%.
Dihydropyrimidines can also be dehydrogenated with nitrobenzene. For example, as described by T. Kauffmann, Angew. Chem. Int. Ed. Engl. 18, 1 (1979), 4-(2'-pyridyl)-3,4-dihydropyrimidine was dehydrogenated with nitrobenzene to produce 4-(2'-pyridyl)pyrimidine in 30% yield.
These methods of synthesis of substituted halogenopyrimidines, in which an organometallic compound is reacted with a halogenopyrimidine and the intermediate dihydro-addition product is isolated before dehydrogenation, under conditions which encourage side product formation, are difficult and inefficient.
It is therefore an object of the present invention to provide an easy, efficient method of synthesis of substituted halogenated diazines which results in a high yield of product.
It is another object of the present invention to provide a method to add a functional group to a halogenodiazine which does not hydrolyze the halogen group.
It is still another object of the present invention to provide novel substituted halogenodiazines which may be used as intermediates in organic synthesis.
It is yet another object of the present invention to provide novel unfused heteropolycyclic compounds having biological activity.